Đăng xuất
Pharmacotherapeutic group: Nonsteroidal anti-inflammatory drugs. ATC code: M01AB05.
Pharmacology: Pharmacodynamics: Diclofenac, a derivative of phenylacetic acid, is a primitive non-steroidal anti-inflammatory drug (NSAID). Diclofenac is structurally related to meclofenamate sodium and meclofenamic acid and pharmacologically similar to other primary NSAIDs. The drug inhibits angiogenesis and degrades nascent blood vessels in inflammatory tissues of animals. NSAIDs, including diclofenac, are predicted to inhibit angiogenesis through inhibition of substrate P or inhibition of the angiogenic effects of prostaglandin E (PEG). The drug has anti-inflammatory, analgesic and antipyretic effects. The exact mechanism has not been clearly established, but many effects are associated primarily with inhibition of prostaglandin synthesis. Diclofenac inhibits prostaglandin synthesis in body tissues by inhibiting cyclooxygenase; at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (prostaglandin G/H synthase-1 [PGHS-1] and -2 [PGHS-2], respectively), which catalyze the synthesis of prostaglandin formation in the arachidonic acid pathway. Diclofenac, like other primary NSAIDs, inhibits both COX-1 and COX-2. Although the exact mechanism has not been clearly established, NSAIDs exert their anti-inflammatory, analgesic and antipyretic effects mainly through inhibition of the COX-2 isoenzyme; COX-1 inhibition is probably responsible for the undesirable effects of the drug on the gastrointestinal mucosa and platelet aggregation.
Pharmacokinetics: Absorption: Diclofenac is rapidly and efficiently absorbed after conventional oral, rectal or intramuscular administration.
Maximal plasma concentrations after rectal administration are attained after approximately thirty minutes. Peak plasma concentrations and area under the plasma concentration-time curve (AUC) are linearly related to a dose over the range of 25 - 150 mg, regardless of administration route; after oral, rectal or intramuscular doses no accumulation occurred after repeated doses.
In elderly patients of more than 62 years of age and patients aged 2 - 7 years with juvenile rheumatoid arthritis peak plasma concentrations, time to peak plasma concentrations (tmax) and AUC values are similar to those produced in adult patients without arthritic conditions.
Bioavailability: The systemic bioavailability of diclofenac from the delayed-release dosage form is averaging about 82% of that of enteric coated tablets at the same dose (possibly depending on the rate of release due to first-pass metabolism). As a result of the slower release of the active substance, peak plasma concentrations are lower than that of the corresponding enteric coated tablets.
Pharmacokinetic behaviour does not change on repeated administration. Accumulation does not occur, provided the recommended dosage intervals are observed. The trough concentration of diclofenac in plasma after administration of 100 mg/day extended-release tablets is approximately 22 ng/ml (70 nmol/l).
Distribution: The active substance is 99.7% protein bound, mainly to albumin (99.4%).
Diclofenac enters the synovial fluid, where maximum concentrations are measured 2-4 hours after the peak plasma values have been attained. The apparent half-life for elimination from the synovial fluid is 3-6 hours. Two hours after reaching the peak plasma values, concentrations of the active substance are already higher in the synovial fluid than they are in the plasma and remain higher for up to 12 hours.
Metabolism: Biotransformation of diclofenac takes place partly by glucuronidation of the intact molecule, but mainly by single and multiple hydroxylation and methoxylation, resulting in several phenolic metabolites, most of which are converted to glucuronide conjugates. Two phenolic metabolites are biologically active, but to a much lesser extent than diclofenac.
Elimination: The total systemic clearance of diclofenac in plasma is 263 ± 56 mL/min (mean value ± SD). The terminal half-life in plasma is 1-2 hours. Four of the metabolites, including the two active ones, also have short plasma half-lives of 1-3 hours.
About 60% of the administered dose is excreted in the urine in the form of the glucuronide conjugate of the intact molecule and as metabolites, most of which are also converted to glucuronide conjugates. Less than 1% is excreted as unchanged substance. The rest of the dose is eliminated as metabolites through the bile in the faeces.
